The mission of the Radiation Epidemiology Branch (REB) is to identify, quantify, and understand the risk of cancer in populations exposed to radiation, alone or in combination with other agents, such as cytotoxic drugs. This includes research directed to filling important gaps in our knowledge of the relation between radiation dose and site-specific carcinogenesis. In the proposed initiative, REB will provide new information on the relation between radiation dose and cancer risk for three gastrointestinal (GI) organs (stomach, esophagus, and pancreas) for which few quantitative data exist. The study will also supply important new information relevant to clinical decision-making, as it will be undertaken in cancer survivors, and constitutes the first analytic investigation of second GI tumors incorporating information on radiation dose and chemotherapy. This setting will also permit REB to address a major goal in the Branch Strategic Plan - research directed to improving the scientific community's understanding of multiple primary cancers. Second or higher order cancers now represent the most common category of tumors reported to the NCI Surveillance, Epidemiology, and End Results (SEER) Program, accounting for over 16% of all incident cancers in 2003, a burgeoning number which reflects the increasing number of long-term survivors and the late effects of therapy. In the proposed initiative, case-control studies of three highly lethal GI malignancies will be conducted among cancer survivors reported to population-based cancer registries, utilizing methods and contracting mechanisms successfully implemented in numerous prior investigations. The major study objectives are to provide new quantitative information on the relation between radiation dose and the subsequent risk of cancers of stomach, esophagus, and pancreas; and to generate new data on the long-term temporal patterns of radiation-related GI cancers and the possible influence of age and chemotherapy. In addition, available biologic samples will be collected to identify common genetic variants that may predispose to the risk of developing radiotherapy-induced second cancers.